The development of prophylactic and therapeutic HIV vaccines remains an important goal, and CD8 T cell responses represent a critical component of the adaptive immune response mediating control of HIV. This is supported by the strong association observed between specific HLA class I alleles and slower disease progression. Coincidentally, the MHC class I alleles most associated with control of HIV and SIV all target conserved epitopes within the capsid proteins and loss of control in the setting of these alleles is associated with the development of CD8 escape mutations in the dominant CD8 epitopes restricted by these alleles. Thus, one hypothesis is that HIV is unable to evade these responses due to the difficulty of escaping from conserved epitopes, which would otherwise alter capsid structure and reduce viral replication capacity. Studies have highlighted the importance of binding of the host protein cyclophilin A (CypA) to the viral capsid for infectivity, and recent reports also now implicate a role for CypA in blocking access of host resistance factors, which represent a class of proteins shown to confer substantial host resistance to retroviral infections. Therefore, control may actually be mediated through mutations disrupting binding of CypA and removing the block to host restriction factors (Ref1/TRIM5a). Notably, each of the MHC alleles associated with control induce mutations within and around the CypA binding loop, and our preliminary work reveals that these escape mutations do limit viral replication, but are dependent upon CypA levels. Therefore, this proposal will examine the relationship between CD8-associated mutations in capsid and removal of the block to host restriction factors. Specifically, we plan to i) Determine the impact of B57-TW10, B27-KK10, and Mm-A01-CM9 escape and compensatory mutations on capsid stability, CypA binding, host restriction factors, and viral fitness, and ii) Utilize primary isolates to determine whether control of HIV-1 replication is associated with alterations in capsid stability, CypA binding, host restriction factors, or fitness. If cyclophilin A binding and host restriction factor activity is related to protective HLA alleles this would reveal a novel link between adaptive and innate immunity, providing novel therapeutic approaches to control HIV.